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D A Cox

Publications and source records attributed to D A Cox.

At least 19 recordsLinked to original sources
PubMed2002

Selective estrogen receptor modulators: tissue actions and potential for CNS protection.

Significant physiologic changes occur during menopause. Evidence exists to suggest that estrogen may be neuroprotective under specific conditions. However, there are limitations in the neuroprotection afforded by standard hormone therapy. Accordingly, alternative agents with selected estrogenic effects may hold even greater promise rather than conventional hormone replacement therapy for the prevention and treatment of CNS injury. Recently, a variety of selective estrogen receptor modulators (SERMs) have been developed to retain the favorable and minimize the adverse side effects of estrogens. This review focuses on the CNS and known neuroprotective effects of two specific SERMs, raloxifene and arzoxifene. Recent studies hint that raloxifene and arzoxifene are neuroprotective and may preserve some elements of cognitive function. However, the mechanism of action is not well described and it is unclear if the beneficial effects of SERMs rely on activation of estrogen receptors.

Animals↗
PubMed2001

Cost-effectiveness of coronary stenting in acute myocardial infarction: results from the stent primary angioplasty in myocardial infarction (stent-PAMI) trial.

BACKGROUND: Although several randomized trials have demonstrated that coronary stenting improves angiographic and clinical outcomes for patients with acute myocardial infarction (AMI), the cost-effectiveness of this practice is unknown. The objective of the present study was to evaluate the long-term costs and cost-effectiveness (C/E) of coronary stenting compared with primary balloon angioplasty as treatment for AMI. Methods and Results- Between December 1996 and November 1997, 900 patients with AMI were randomized to undergo balloon angioplasty (PTCA, n=448) or coronary stenting (n=452). Detailed resource utilization and cost data were collected for each patient's initial hospitalization and for 1 year after randomization. Compared with conventional PTCA, stenting increased procedural costs by approximately $2000 per patient ($6538+/-1778 versus $4561+/-1598, P<0.001). During the 1-year follow-up period, stenting was associated with significant reductions in the need for repeat revascularization and rehospitalization. Although follow-up costs were significantly lower with stenting ($3613+/-7743 versus $4592+/-8198, P=0.03), overall 1-year costs remained approximately $1000/patient higher with stenting than with PTCA ($20 571+/-10 693 versus 19 595+/-10 990, P=0.02). The C/E ratio for stenting compared with PTCA was $10 550 per repeat revascularization avoided. In analyses that incorporated recent changes in stent technology and pricing, the 1-year cost differential fell to <$350/patient, and the C/E ratio improved to $3753 per repeat revascularization avoided. The cost-utility ratio for primary stenting was <$50 000 per quality-adjusted life year gained only if stenting did not increase 1-year mortality by >0.2% compared with PTCA. CONCLUSIONS: As performed in Stent-PAMI, primary stenting for AMI increased 1-year medical care costs compared with primary PTCA. The overall cost-effectiveness of primary stenting depends on the societal value attributed to avoidance of symptomatic restenosis, as well as on the relative mortality rates of primary PTCA and stenting.

Aged↗
PubMed2001

Importance of time to reperfusion on outcomes with primary coronary angioplasty for acute myocardial infarction (results from the Stent Primary Angioplasty in Myocardial Infarction Trial).

The mortality benefit of thrombolytic therapy for acute myocardial infarction (AMI) is strongly dependent on time to treatment. Recent observations suggest that time to treatment may be less important with primary percutaneous transluminal coronary angioplasty (PTCA). Patients with AMI of <12 hours duration, without cardiogenic shock, who were treated with primary PTCA from the Stent PAMI Trial (n = 1,232) were evaluated to assess the effect of time to reperfusion on outcomes. Thrombolysis In Myocardial Infarction grade 3 flow was achieved in a high proportion of patients regardless of time to treatment. Improvement in ejection fraction from baseline to 6 months was substantial with reperfusion at <2 hours but was modest and relatively independent of time to reperfusion after 2 hours (<2 hours, 12.3% vs > or =2 hours, 4.2%, p = 0.004). There were no differences in 1- or 6-month mortality by time to reperfusion (6-month mortality: <2 hours [5.5%], 2 to <4 hours [4.6%], 4 to <6 hours [4.5%], >6 hours [4.2%], p = 0.97). There were also no differences in other clinical outcomes by time to reperfusion, except that reinfarction and infarct artery reocclusion at 6 months were more frequent with later reperfusion. The lack of correlation between time to treatment and mortality in patients without cardiogenic shock suggests that the survival benefit of primary PTCA may be related principally to factors other than myocardial salvage. These data may also have implications regarding the triage of patients with AMI for primary PTCA.

Aged↗
PubMed2001

Quality of life after balloon angioplasty or stenting for acute myocardial infarction. One-year results from the Stent-PAMI trial.

OBJECTIVES: The goal of this study was to compare the impact of primary stenting or percutaneous transluminal coronary angioplasty (PTCA) on health-related quality of life (HRQOL) in patients undergoing direct angioplasty for acute myocardial infarction (AMI). BACKGROUND: Previous studies have demonstrated that coronary stenting reduces clinical and angiographic restenosis compared with PTCA. However, the impact of stenting on HRQOL from the patient's perspective remains unknown. METHODS: We administered the Seattle Angina Questionnaire and the Medical Outcomes Study Short-form Survey at 1, 6 and 12 months after initial treatment to all North American patients in the Stent-Primary Angioplasty for Myocardial Infarction trial (Stent-PAMI) (n = 509)-a randomized trial comparing primary stenting to conventional PTCA for patients with AMI. RESULTS: At one month, most HRQOL measures were similar for the two groups, but stent patients reported less bodily pain than PTCA patients (p = 0.03). At six-month follow-up, stenting resulted in significant improvements in several dimensions of HRQOL including reduced anginal frequency and bodily pain as well as improved disease perception (all p < or = 0.03) and a trend towards better anginal stability (p = 0.056). By 12-month follow-up, however, none of these differences remained statistically significant. These differences in HRQOL were largely explained by the greater need for ischemia-driven target-vessel repeat revascularization procedures in PTCA patients during the first six months (16.0% vs. 6.2%, p < 0.001). CONCLUSIONS: In patients undergoing revascularization for AMI, initial stent placement is associated with improvements in several dimensions of health status during the first six months of follow-up. In the absence of differences in mortality, these findings add to the overall argument in favor of initial stenting in patients treated with mechanical reperfusion for myocardial infarction.

Angioplasty, Balloon, Coronary↗
PubMed2001

Effects of raloxifene and hormone replacement therapy on markers of serum atherogenicity in healthy postmenopausal women.

OBJECTIVE: To determine the effect of raloxifene (RLX) and hormone replacement therapy (HRT) on non-high density lipoprotein cholesterol (non-HDL-C) levels and the apolipoprotein-B/apolipoprotein-A1 (apo-B/apo-A1) concentration ratio, markers of serum atherogenicity, in postmenopausal women. METHODS: Three hundred and ninety healthy postmenopausal women aged 45-72 years were enrolled in a double-blind, randomized, placebo-controlled, parallel trial at eight outpatient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), 60 or 120 mg/day raloxifene, or placebo for 6 months. Serum concentrations of non-HDL cholesterol and the apo-B/apo-A1 concentration ratio were measured in serum samples obtained at baseline and at 6 months of treatment. RESULTS: At 6 months, non-HDL-C and apo-B/apo-A1 were significantly reduced by 60 mg/day RLX (10 and 11%, respectively), 120 mg/day RLX (9 and 12%, respectively) and HRT (10 and 12%, respectively), compared with placebo. The effect of all treatments to lower non-HDL-C and apo-B/apo-A1 was greatest in women with hypercholesterolemia (total-C>240 mg/dl) at baseline. Among women with undesirable (>160 mg/dl) non-HDL cholesterol at baseline, RLX and HRT lowered the percentage of these women remaining above this threshold after 6 months (placebo, 89%; 60 mg/day RLX, 61%; 120 mg/day RLX, 74%; HRT, 58%). Similar results were observed for women with high (>190 mg/dl) non-HDL cholesterol at baseline. CONCLUSION: In healthy postmenopausal women, RLX and HRT lower serum non-HDL-C and apo-B/apo-A1, indicators of serum atherogenicity, to a similar extent.

Aged↗
PubMed2001

Cognitive function in postmenopausal women treated with raloxifene.

BACKGROUND: In postmenopausal women, estrogen may have a beneficial effect on cognition or reduce the risk of decline in cognitive function. Whether raloxifene, a selective estrogen-receptor modulator, might have similar actions is not known. METHODS: As part of the Multiple Outcomes of Raloxifene Evaluation trial, we studied 7478 postmenopausal women with osteoporosis (mean age, 66 years), who were enrolled at 178 sites in 25 countries. The women were randomly assigned to receive raloxifene (60 mg or 120 mg) or placebo daily for three years. We compared the mean scores of the groups on six tests of cognitive function, which were administered at base line and at six months and one, two, and three years. Women were classified as having a decline in cognitive function if the change in their scores at three years was in the worst 10 percent. RESULTS: The mean cognitive scores in the three groups of women were similar at base line. The scores improved slightly in all three groups during the three-year study period, with no significant differences among the groups. The risk of decline in the cognitive function, as measured by four of the six tests, did not differ significantly between the two raloxifene groups combined and the placebo group, but there was a trend toward less decline in the combined raloxifene group on the two tests of verbal memory (relative risk, 0.77) and attention, (relative risk, 0.87). Newly reported or worsening hot flashes did not negatively influence test scores or the effect of treatment on test performance. CONCLUSIONS: Raloxifene treatment for three years does not affect overall cognitive scores in postmenopausal women with osteoporosis.

Aged↗
PubMed2001

Effect of raloxifene on serum triglycerides in postmenopausal women: influence of predisposing factors for hypertriglyceridemia.

BACKGROUND: Estrogen increases serum triglyceride (TG) levels and induces hypertriglyceridemia in susceptible women. The effect of raloxifene (RLX), a selective estrogen-receptor modulator, on serum TG has not been studied in detail. OBJECTIVE: The purpose of this study was to examine the effect of RLX on serum TG levels in postmenopausal women with and without osteoporosis, including those with predisposing factors for hypertriglyceridemia. METHODS: Fasting serum TG levels were assessed over 36 months in 2738 osteoporotic postmenopausal women (mean age, 67 years) assigned to placebo or RLX (60 or 120 mg/d) in an osteoporosis treatment trial and over 24 months in 1318 postmenopausal women without osteoporosis (mean age, 54 years) assigned to placebo or RLX (60 or 150 mg/d) in 3 osteoporosis prevention trials. RESULTS: In the osteoporosis treatment trial, the median serum TG concentration decreased in all groups, but significantly more in the placebo group (placebo, -3.4%; RLX 60 mg/d, -1.4%; RLX 120 mg/d, -1.3%; P = 0.002). In the osteoporosis prevention trials, the percentage change in median serum TG concentration was not significantly different among treatments (P = 0.22). Among women with varying degrees of hypertriglyceridemia at baseline (>2.82, >3.39, and >4.51 mmol/L), the median serum TG level at the end of the study decreased from baseline in all groups, with no significant differences among treatments (P > or = 0.13). The effect of RLX on serum TG level was not influenced by age, smoking status, use of alcohol, or presence of diabetes (P > or = 0.10 for all interactions). Among women in the highest tertile of body mass index (>26.4 kg/m2), RLX increased serum TG levels significantly compared with placebo (placebo, -3%; RLX 60 mg/d, 6%: RLX 120 mg/d, 4%; P < 0.05); the absolute increase from baseline with RLX in this subgroup was 0.05 mmol/L (4.4 mg/dL). CONCLUSIONS: RLX did not increase serum TG in postmenopausal women overall or among women with elevated TG levels or evidence of diabetes at baseline. TG levels increased slightly but statistically significantly in women in the upper tertile of body mass index who were treated with RLX.

Adult↗
PubMed2001

An assessment of the toxicity of phthalate esters to freshwater benthos. 1. Aqueous exposures.

Tests were performed with the freshwater invertebrates Hyalella azteca, Chironomus tentans, and Lumbriculus variegatus to determine the acute toxicity of six phthalate esters, including dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP), di-n-hexyl phthalate (DHP), and di-2-ethylhexyl phthalate (DEHP). It was possible to derive 10-d LC50 (lethal concentration for 50% of the population) values only for the four lower molecular weight esters (DMP, DEP, DBP, and BBP), for which toxicity increased with increasing octanol-water partition coefficient (Kow) and decreasing water solubility. The LC50 values for DMP, DEP, DBP, and BBP were 28.1, 4.21, 0.63, and 0.46 mg/L for H. azteca; 68.2, 31.0, 2.64, and > 1.76 mg/L for C. tentans; and 246, 102, 2.48, and 1.23 mg/L for L. variegatus, respectively. No significant survival reductions were observed when the three species were exposed to either DHP or DEHP at concentrations approximating their water solubilities.

Animals↗
PubMed2001

An assessment of the toxicity of phthalate esters to freshwater benthos. 2. Sediment exposures.

Seven phthalate esters were evaluated for their 10-d toxicity to the freshwater invertebrates Hyalella azteca and Chironomus tentans in sediment. The esters were diethyl phthalate (DEP), di-n-butyl phthalate (DBP), di-n-hexyl phthalate (DHP), di-(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), and a commercial mixture of C7, C9, and C11 isophthalate esters (711P). All seven esters were tested in a sediment containing 4.80% total organic carbon (TOC), and DBP alone was tested in two additional sediments with 2.45 and 14.1% TOC. Sediment spiking concentrations for DEP and DBP were based on LC50 (lethal concentration for 50% of the population) values from water-only toxicity tests, sediment organic carbon concentration, and equilibrium partitioning (EqP) theory. The five higher molecular weight phthalate esters (DHP, DEHP, DINP, DIDP, 711P), two of which were tested and found to be nontoxic in water-only tests (i.e., DHP and DEHP), were tested at single concentrations between 2,100 and 3,200 mg/kg dry weight. Preliminary spiking studies were performed to assess phthalate ester stability under test conditions. The five higher molecular weight phthalate esters in sediment had no effect on survival or growth of either C. tentans or H. azteca, consistent with predictions based on water-only tests and EqP theory. The 10-d LC50 values for DBP and H. azteca were >17,400, >29,500, and >71,900 mg/kg dry weight for the low, medium, and high TOC sediments, respectively. These values are more than 30x greater than predicted by EqP theory and may reflect the fact that H. azteca is an epibenthic species and not an obligative burrower. The 10-d LC50 values for DBP and C. tentans were 826, 1,664, and 4.730 mg/kg dry weight for the low, medium, and high TOC sediments, respectively. These values are within a factor of two of the values predicted by EqP theory. Pore-water 10-d LC50 values for DBP (dissolved fraction) and C. tentans in the three sediments were 0.65, 0.89, and 0.66 of the water-only LC50 value of 2.64 mg/L, thereby agreeing with EqP theory predictions to within a factor of 1.5. The LC50 value for DEP and C. tentans was >3,100 mg/kg dry weight, which is approximately 10x that predicted by EqP theory. It is postulated that test chemical loss and reduced organism exposure to pore water may have accounted for the observed discrepancies with EqP calculations for DEP

Animals↗
PubMed2000

Raloxifene, an oestrogen-receptor modulator, prevents decreased constitutive nitric oxide and vasoconstriction in ovariectomized rats.

Administration of graded doses of [Arg(8)]vasopressin (0.06-0.18 microg kg(-1), i.v.) induced a dose-dependent increase in arterial blood pressure in the catecholamine-depleted (phentolamine; 10 mg kg(-1), i.p.) intact and ovariectomized female rat, with the elevation of blood pressure more marked following ovariectomy. In addition, ovariectomy caused the down-regulation of aortic Ca(2+)-dependent constitutive nitric oxide synthase (assessed by the citrulline assay). The down-regulation of the Ca(2+)-dependent constitutive nitric oxide synthase and augmentation of vasopressin-induced blood pressure responses were prevented by the therapy (1 month, p.o.) with the selective oestrogen receptor modulator, raloxifene (0.3-1.0 mg kg(-1) day(-1)), or with 17beta-oestradiol (0.3 mg kg(-1) day(-1)) in ovariectomized rats. Thus, oestrogen deficiency down-regulates vascular constitutive nitric oxide synthase, which appears to be involved in the increased sensitivity of the vasculature to vasopressin, since both effects can be reversed by the exogenous administration of the natural oestrogen 17beta-oestradiol or the selective oestrogen-receptor modulator raloxifene.

Animals↗
PubMed2000

Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the primary angioplasty in myocardial infarction trials).

Advanced age is associated with increased mortality in acute myocardial infarction (AMI) but the mechanism remains unclear. We performed a pooled analysis of 3,032 patients from the Primary Angioplasty in Myocardial Infarction (PAMI)-2, Stent-PAMI, and PAMI-No Surgery On Site trials to determine which clinical, hemodynamic, and angiographic characteristics in the elderly were associated with in-hospital death. There were 452 patients aged >/=75 years and 2,580 patients aged <75 years. Older patients had a lower number of risk factors for coronary artery disease but more comorbidities. Acute catheterization demonstrated more 3-vessel disease, higher left ventricular (LV) end-diastolic pressure, lower LV ejection fraction, and higher initial rates of Thrombolysis In Myocardial Infarction (TIMI) trial 2 or 3 flow. Elderly patients were equally likely to undergo percutaneous intervention but had a lower procedural success rate and lower rates of final TIMI 3 flow, and older patients were more likely to have post-AMI complications. In-hospital mortality was 10.2% and 1.8%, respectively (p = 0.001). Cardiac and noncardiac mortality was higher in elderly patients, and no significant differences in causes of death were identified. Multivariate analysis revealed that the strongest predictors of death were age >/=75 years, lower LV ejection fraction, lower final TIMI flow, higher Killip class, need for an intra-aortic balloon pump (IABP), and post-AMI stroke/transient ischemic attack, or significant arrhythmia. Despite avoiding thrombolysis, elderly patients remain at increased risk of bleeding, stroke, and other post-AMI complications, and death. Cardiac risk factor analysis and acute catheterization offer prognostic information but do not completely explain the mechanism of increased in-hospital mortality in the elderly.

Aged↗
PubMed2000

Raloxifene and estrogen inhibit neointimal thickening after balloon injury in the carotid artery of male and ovariectomized female rats.

The effects of raloxifene and 17alpha-ethinyl estradiol (EE2) on intimal thickening in response to balloon injury were tested in male and ovariectomized female rats. In male rats, oral raloxifene and EE2, administered either by gavage or in the diet, inhibited arterial intimal thickening in response to balloon injury to a maximum of approximately 60 and 50%, respectively. The effect of oral raloxifene to decrease cholesterol was observed at doses (> or = 3 mg/kg/day) higher than those required to inhibit intimal thickening (> or = 0.03 mg/kg/day). Coadministration of the estrogen receptor antagonist, ICI 182,780 (5 mg/kg/day, s.c.), blocked the inhibition of balloon injury by raloxifene and EE2. Direct adventitial delivery of raloxifene (0.03 mg/kg/day) and EE2 (0.001 mg/kg/day) to the vascular wall inhibited intimal thickening by 63 and 53%, respectively. In ovariectomized female rats, oral raloxifene (0.01-3.0 mg/kg/day) and EE2 (0.08 mg/kg/day) inhibited intimal thickening to a maximum of 32 and 60%, respectively. Together, these data suggest that raloxifene and EE2, inhibit balloon arterial injury in the rat through direct effects on the vascular wall that involve the estrogen receptor and are at least partially independent of serum cholesterol.

Animals↗
PubMed2000

Raloxifene therapy.

Explore the source record for details and available documents.

Accidental Falls↗
PubMed2000

The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial.

C-Reactive protein and homocysteine are independent risk factors for the development of cardiovascular disease. This study compared the effects of hormone replacement therapy (HRT) and raloxifene on serum C-reactive protein and homocysteine levels as markers of cardiovascular risk in healthy postmenopausal women. Healthy postmenopausal women (n = 390) were enrolled in a double blind, randomized, placebo-controlled, 6-month trial at eight out-patient sites in the United States. Women were randomly assigned to receive continuous combined HRT (0.625 mg/day conjugated equine estrogen and 2.5 mg/day medroxyprogesterone acetate), raloxifene (60 or 120 mg/day), or placebo for 6 months. C-Reactive protein and homocysteine were measured in baseline and 6-month serum samples. HRT increased C-reactive protein levels by 84% (P<0.001), whereas raloxifene (60 and 120 mg/day) had no significant effect (-6% and -4%;, respectively; P>0.2). Raloxifene (60 and 120 mg/day) significantly lowered serum levels ofhomocysteine by 8% (P = 0.014) and 6% (P = 0.024), respectively, similar to the 7% (P = 0.014) reduction obtained with HRT. We conclude that HRT and raloxifene lower serum homocysteine levels to a comparable extent in postmenopausal women. Whereas cardiovascular risk predicted by C-reactive protein in healthy postmenopausal women is not influenced by raloxifene, the relationship between elevated C-reactive protein levels with HRT and cardiovascular disease events requires further study.

Aged↗
PubMed1999

Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group.

BACKGROUND: Coronary-stent implantation is frequently performed for treatment of acute myocardial infarction. However, few studies have compared stent implantation with primary angioplasty alone. METHODS: We designed a multicenter study to compare primary angioplasty with angioplasty accompanied by implantation of a heparin-coated Palmaz-Schatz stent. Patients with acute myocardial infarction underwent emergency catheterization and angioplasty. Those with vessels suitable for stenting were randomly assigned to undergo angioplasty with stenting (452 patients) or angioplasty alone (448 patients). RESULTS: The mean (+/-SD) minimal luminal diameter was larger after stenting than after angioplasty alone (2.56+/-0.44 mm vs. 2.12+/-0.45 mm, P<0.001), although fewer patients assigned to stenting had grade 3 blood flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) (89.4 percent, vs. 92.7 percent in the angioplasty group; P=0.10). After six months, fewer patients in the stent group than in the angioplasty group had angina (11.3 percent vs. 16.9 percent, P=0.02) or needed target-vessel revascularization because of ischemia (7.7 percent vs. 17.0 percent, P<0.001). In addition, the combined primary end point of death, reinfarction, disabling stroke, or target-vessel revascularization because of ischemia occurred in fewer patients in the stent group than in the angioplasty group (12.6 percent vs. 20.1 percent, P<0.01). The decrease in the combined end point was due entirely to the decreased need for target-vessel revascularization. The six-month mortality rates were 4.2 percent in the stent group and 2.7 percent in the angioplasty group (P=0.27). Angiographic follow-up at 6.5 months demonstrated a lower incidence of restenosis in the stent group than in the angioplasty group (20.3 percent vs. 33.5 percent, P<0.001). CONCLUSIONS: In patients with acute myocardial infarction, routine implantation of a stent has clinical benefits beyond those of primary coronary angioplasty alone.

Angioplasty, Balloon, Coronary↗
PubMed1999

Comparative toxicity of fluoranthene to freshwater and saltwater species under fluorescent and ultraviolet light.

The acute and chronic toxicity of fluoranthene was determined for a diverse group of freshwater and saltwater species under both standard laboratory fluorescent light and ultraviolet (UV) light test conditions. Acute tests with 21 species demonstrated that fluoranthene was not lethal within its water solubility limit to most species tested under fluorescent light, but was lethal well below this limit to nearly all of the species tested under UV light. In general, the acute sensitivity of freshwater and saltwater species from the same class was similar, although UV light exposure changed the relative sensitivity of some species. Crustaceans were the most sensitive to fluoranthene, but in the presence of UV light, an oligochaete and a fish were the most sensitive. Overall, UV light increased acute fluoranthene toxicity approximately one to three orders of magnitude. In chronic tests, sublethal concentrations of fluoranthene were toxic under both fluorescent and UV light, but as in most acute tests, UV light increased chronic toxicity approximately an order of magnitude. Comparison of data from tests conducted in the laboratory and outdoors demonstrated that acute toxicity increased with increased UV light intensity.http://link. springer-ny.com/link/service/journals/00244/bibs/37n4p496.++ +html</HEA

Animals↗